This invention relates to antibacterial agents and is particularly concerned with novel, semi-synthetic, 2-deoxystreptamine aminoglycosides and with methods for their preparation. Known 2-deoxystreptamine aminoglycosides include such valuable chemotherapeutic agents as the kanamycins, gentamicin, tobramycin, ribostamycin and the neomycins.
The novel antibacterial agents of this invention are a series of 2-deoxystreptamine aminoglycosides in which the amino group on the 1-position is substituted with an alkyl group bearing one or more hydroxyl groups on carbon atoms other than that linked to the amino group. Such compounds are effective in treating a variety of gram-positive and gram-negative bacterial infections, including urinary tract infections, in animals, including humans, and they possess advantages in use over 2-deoxystreptamine aminoglycosides having an unsubstituted amino group in the 1-position of the 2-deoxystreptamine ring. In particular, the compounds of the invention have been found to posses properties associated with a lower toxicity than many known aminoglycosides.
Belgian Pat. No. 818,431 and U.S. Pat. No. 4,002,742 disclose derivatives of gentamicins A, B.sub.1, C.sub.1, C.sub.1.alpha., C.sub.2, C.sub.2.alpha., C.sub.2.beta. and X.sub.2 ; sisomicin, verdamicin; tobramycin; antibiotics G-418, 66-40B, 66-40D, J1-20A, J1-20B and G-52; and mutamicins 1, 2, 4, 5 and 6, substituted on the 1-amino function. Among the broad terms mentioned for the 1-amino substituent is "hydroxyalkyl". However, Belgian Pat. No. 818,431 and U.S. Pat. No. 4,002,742 do not disclose any compounds having more than one hydroxy in the alkyl group on the 1-amino function, and they do not disclose any compounds possessing the specific monohydroxyalkyl groups of the present invention. In particular, Belgian Pat. No. 818,431 and U.S. Pat. No. 4,002,742 do not disclose any compounds with monohydroxyalkyl groups in which there is branching at the carbon atom adjacent to the nitrogen atom of the 1-amino function. Additionally, Belgian Pat. No. 818,431 and U.S. Pat. No. 4,002,742 do not disclose any kanamycin derivatives.
Belgian Pat. No. 835,898 and U.S. Pat. No. 4,000,261 disclose 5-epi aminoglycoside derivatives, including kanamycins A and B and tobramycin, having a hydroxyalkyl group on the 1-amino function. However, there is no disclosure of alkyl groups substituted with more than one hydroxy group, and there is no specific disclosure of hydroxyalkyl groups which have branching at the carbon atom adjacent to the nitrogen atom of the 1-amino function.
U.S. Pat. No. 4,000,262 discloses 1-N-hydroxyalkyl derivatives of 5-epi-azido-5-deoxy-kanamycins A and B, 5-epi-amino-5-deoxy-kanamycins A and B, 5-epi-azido-5-deoxy-tobramycin and 5-epi-amino-5-deoxy-tobramycin.
U.S. Pat. No. 4,085,208 discloses 1-N-hydroxyalkyl derivatives of 1-epi-kanamycins A and B and 1-epi-tobramycin.
Belgian Pat. No. 834,864 discloses derivatives of 2-deoxystreptamine aminoglycoside antibiotics which have an .omega.-amino-2-hydroxyalkyl group on the 1-amino function.
U.S. Pat. Nos. 3,282,783 and 3,350,387 and British Pat. No. 1,033,394 disclose a broad genus of N-alkylated derivatives of aminoglycoside antibiotics, including derivatives of the kanamycins and tobramycin, in which said N-alkyl groups can contain hydroxy groups. However, these N-alkylated derivatives are reported to be substantially devoid of antibiotic properties by virtue of this alkylation.